Due to the high rate of infection and mortality that characterizes COVID-19 in older adults and with risk factors, it has been studied the mechanism by which it affects the elderly population in a greater proportion. It has been observed that there is a relationship between mitochondrial dysfunction and the sepsis it generates.

COVID-19 is associated with acute inflammation, hypoxia, acidosis, hypercoagulability, and glycolytic metabolism, which implies increased lactic acid concentrations and decreased intracellular pH [1]. Also, when metabolism is altered, there is an excess of reactive oxygen species (EROS). [2]

Using a computational model, Kevin E. Wu and his team from Stanford University propose that the virus stays in the mitochondria and nucleolus. They predict that this localization is due to the need for the formation of double-membrane vesicles, which the virus uses to replicate itself and evade the immune system. For this reason, once inside the cell it would “kidnap” mitochondria and use its machinery to replicate and subsist. The structure of these organelles would be damaged, with the consequent release of mitochondrial DNA into the cell cytoplasm, which would trigger the immune response.

The viral activation mechanism is similar to that generated by endogenous damage marker molecules (DAMPs). By activating Toll-like receptors, it triggers an immune response that involves the activation of neutrophils, macrophages, dendritic cells, and NK lymphocytes. In addition, it includes the transcription and expression of genes such as prostaglandins, proinflammatory cytokines, chemokines, and interleukins, which activate the complement system and the pro-inflammatory cascade. [3]

Therefore, if COVID-19 attacks and manipulates the mitochondria in order to maintain its life cycle, it could be explained why patients with a higher proportion of senescent tissue and suboptimal immune cells are especially susceptible and unable to follow the hypermetabolic rhythm sudden virus generated, which is associated with sepsis. Evidence on animal models suggests that Hyperbaric Oxygen Therapy (HBOT) in early instances generates a critical improvement in this condition, thanks to the reduction of the inflammatory response triggered by the virus.

Hyperbaric Oxygen Therapy is capable of raising arterial oxygen levels and, unlike respirators, raising the concentration of oxygen that accesses the tissues. This increase provides the cells with stimulating signals for the expression of transcription factors such as Nrf2, which stimulates the production of immune cells, or HSF1 (Heat shock factor 1), which stimulates the expression of anti-inflammatory proteins. [4]

Hyperoxia triggered by Hyperbaric Oxygen preserves the cellular metabolism and the normal function of the organs. HBOT has been shown to improve mitochondrial functionality. [5]

According to Tezgin et.al, it alters the balance between glycolysis and mitochondrial respiration, possibly counteracting an effect of the viral infection that generates hypoxia in COVID-19 positive patients. [6]

Another benefit of the application of Hyperbaric Oxygenation Treatment is the decrease in the inflammatory response, the toll-type inflammatory markers, and in levels of TNF-alpha (a factor that blocks the cellular respiratory chain). [4]

Hyperbaric oxygen works by restoring the functionality of the mitochondria, increasing oxygenation, and activating mitophagy or elimination of damaged mitochondria. It could contribute to recovering the mitochondrial damage produced in COVID-19 and, together with its already documented anti-inflammatory effect, attenuate or reduce the inflammation in these patients.

This way, hyperbaric oxygenation constitutes a powerful oxygenation tool in patients with COVID-19 because it increases saturation, prevents, and recovers hypoxemia. In addition, it helps to reduce the mitochondrial damage caused by the virus that leads to severe complications.

 

Sources

 

[1] Shenoy, S. Coronavirus (Covid-19) sepsis: revisiting mitochondrial dysfunction in pathogenesis, aging, inflammation, and mortality. Inflamm. Res. 69, 1077–1085 (2020). https://doi.org/10.1007/s00011-020-01389-z

[2] Zhou Q, Huang G, Yu X, Xu W: A Novel Approach to Estimate ROS Origination by Hyperbaric Oxygen Exposure, Targeted Probes and Specific Inhibitors. Cell Physiol Biochem 2018;47:1800-1808. doi: 10.1159/000491061

[3] Wu KE, Fazal FM, Parker KR, et al. RNA-GPS predicts SARS-

CoV-2 RNA residency to host mitochondria and nucleolus. Cell Syst. (2020);11(102–108):e3. https://doi.org/10.1016/j.cels.2020.06.008

[4] De Maio, A., Hightower, L.E. COVID-19, acute respiratory distress syndrome (ARDS), and hyperbaric oxygen therapy (HBOT): Cell Stress and Chaperones 25, 717–720 (2020). https://doi.org/10.1007/s12192-020-01121-0

[5] Tezgin, D., Giardina, C., Perdrizet, G.A. et al. The effect of hyperbaric oxygen on mitochondrial and glycolytic energy metabolism: the caloristasis concept. Cell Stress and Chaperones 25, 667–677 (2020). https://doi.org/10.1007/s12192-020-01100-5

[6] Dave, K. R., Prado, R., Busto, R., Raval, A. P., Bradley, W. G., Torbati, D., & Pérez-Pinzón, M. A. (2003). Hyperbaric oxygen therapy protects against mitochondrial dysfunction and delays onset of motor neuron disease in Wobbler mice. Neuroscience, 120(1), 113–120. https://doi.org/10.1016/s0306-4522(03)00244-6